The general aim of this project is to determine for mammalian cells the molecular mechanisms by which heat kills and radiosensitizes cells. The general approach is to identify quantitative as well as qualitative correlations between morphological lesions, biochemical changes, chromosomal aberrations and cell survival for cells treated in different parts of the cell cycle. Morphological endpoints are being examined using light microscopy (time lapse cinematography), conventional and scanning electron microscopy, freeze fracture techniques, and high voltage electron microscopy. The plasma membrane, intracellular membranes and cytoskeleton are the primary subcellular components being examined. Several biochemical properties of the plasma membrane (fluidity and transport) are also being examined. All studies are being performed with cells in specific stages of the cell cycle and at the same survival level following various perturbations and compared to chromosomal aberrations. The effects of hyperthermia and local anesthetics (procaine-HCl, lidocaine-HCl) on the response of cells to high and low dose rate irradiation, conditions of environmental stress, and ultimately a combination of environmental stress and high dose rate irradiation are to be studied. The results of these studies at the basic research level will add to an understanding of the cellular mechanisms responsible for heat killing and radiosensitization. Such an understanding should be useful in designing therapy protocols for small and large animals and ultimately humans.